The Extracellular signal-Regulated protein Kinase1/2 (ERK1/2, classical MARK) intracellular signal transduction cascade is activated by numerous extracellular stimuli that play important roles in various aspects of nervous system development, plasticity, and regeneration. Although ERK1/2 is thought to be vital for a number of processes its precise functional role has not been adequately analyzed. To better clarify the role of ERK1/2 signaling in peripheral nervous system development, we have utilized Cre/loxp technology to conditionally inactivate ERK1/2 specifically in sensory neurons and Schwann cells at early stages of development. The precise in vivo function of ERK1/2 signaling in Schwann cell differentiation and myelination and sensory neuron axon growth will be defined. The ability of the related kinase, ERK5, to compensate for loss of ERK1/2 will also be analyzed. These data will further our understanding of the complex functions regulated by ERK1/2 in separate cell types and clarify the intracellular pathways utilized by a trophic factors important for nervous system development. Summary Statement: Genetic or sporadic disruption of ERK1/2 signaling has been implicated in craniofacial syndromes, autism spectrum disorders, neuropathic pain, neurofibramatosis, and various cancers, yet our understanding of the functions of this pathway remain incomplete. The data arising from the execution of this proposal will be of interest to clinical disciplines;exploring ERK1/2 or ERK5 signaling as a therapeutic target, seeking to understand the pathogenesis of developmental syndromes resulting from mutations in regulators of ERK1/2 signaling, or attempting to reactivate neuronal or glial programs to induce or modify nervous system regeneration.